通过抗原特异性调节T细胞对HLA相关自身免疫的优势保护
Joshua D Ooi1, Jan Petersen2,3, Yu H Tan2
1Centre for Inflammatory Diseases, Monash University Department of Medicine, Monash Medical Centre, Clayton, Victoria 3168, Australia.
Nature
|May 4, 2017
概括
人类白细胞抗原 (HLA) 的等位基因会影响自身免疫疾病的风险. 这项研究揭示了像HLA-DR15和HLA-DR1这样的特定HLA基因如何决定调节性T细胞的平衡,从而影响自我耐受性和自身免疫性疾病的发展.
科学领域:
- 免疫学
- 遗传学
- 自体免疫性
背景情况:
- 特定的人类白细胞抗原 (HLA) 基因与自身免疫性疾病 (如I型糖尿病,多发性硬化症和Goodpasture疾病) 的易感性和保护有关.
- 通过HLA基因对自我耐受性和自身免疫性疾病发展的影响的精确分子机制仍然不完全理解.
- 良牧病是一种自身免疫性脏疾病,与HLA基因相关,其特征是T细胞对IV型原 (α3135-145) 的特定表位反应.
研究的目的:
- 在Goodpasture疾病的背景下阐明HLA介导的自我耐受性影响的分子机制.
- 研究HLA-DR15 (危险等位基) 和HLA-DR1 (保护性等位基) 在塑造T细胞对α3135-145表位基的反应中的差异性作用.
- 为具有高风险HLA-DR15等位基因的个体提供HLA-DR1的保护作用的机制解释.
主要方法:
- 利用用α3135-145表位素免疫的HLA-DR15转基因小鼠模型研究疾病的发展和T细胞透.
- 分析了HLA-DR15和HLA-DR1的谱和结合偏好.
- 在小鼠模型和人类捐赠者中使用四聚体染色,细胞内细胞因子分析和转录因子 (例如,Foxp3) 鉴定T细胞表型 (Tconv与Treg).
主要成果:
- 在患有Goodpasture病的患者和HLA-DR15转基因小鼠中诱导的疾病中,自主反应的α3135-145特异性T细胞扩大.
- HLA-DR15向常规T细胞 (Tconv) 呈现α3135-145表位,而HLA-DR1诱导的调节性T细胞 (Treg) 表示耐受性细胞因子.
- 在携带HLA-DR15和HLA-DR1等位基因的小鼠中,HLA-DR1诱导的Treg细胞提供了对疾病的保护,而HLA-DR1的健康个体显示出主导的Treg表型.
结论:
- 通过确定亲炎性Tconv细胞和特异性Treg细胞之间的平衡,HLA多态性关键地塑造了免疫反应.
- HLA-DR1的保护作用是由其诱导Treg细胞的能力介导的,这些Treg细胞抑制自身反应,从而预防或减轻自身免疫.
- 这项研究提供了一种机制框架,通过调节特异性T细胞的生成和功能来解释HLA基因如何影响自身免疫性疾病的易感性和保护.
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